By 2010, there will be 12 million cancer survivors in the U.S., with an annual growth rate of 2%. The cumulative incidence of severe or life-threatening chronic health conditions in cancer survivors exceeds 40% at 30 years. This creates an obligation to understand the etiology of these adverse conditions, in order to develop targeted prevention/ intervention strategies and reduce long-term morbidity. Subsequent malignant neoplasms (SMNs) are one of the most devastating adverse events faced by cancer survivors, and are a leading cause of non- relapse mortality. Although, well-defined associations exist between chemoradiotherapy and SMNs (e.g., chemotherapy and therapy-related leukemia; ionizing radiation and subsequent breast or thyroid cancer after Hodgkin lymphoma), there is considerable inter-individual variability, which could be explained by underlying genetic susceptibility - an area that is currently understudied. We have successfully established a mechanism to identify a large number of cancer survivors with SMNs (cases: n=1600) and those without (controls: n=3200). We have also implemented protocols to obtain detailed therapeutic summaries and procure DNA from the cases and controls. Using a case-control study design, this application will explore the role of genetic susceptibility, by examining associations between polymorphisms in specific candidate genes, and the risk of SMN. Because of the well-defined relation between SMNs and specific chemotherapy and ionizing radiation, the focus will be on genes encoding drug metabolizing enzymes, drug-transporter genes, and genes in DNA repair pathways. Based on extensive literature review as well as study of biological pathways involved in DNA repair, and genes involved in drug metabolism and transport of chemotherapeutic agents implicated in SMNs, 771 polymorphisms in 66 genes involved in DNA repair, and 228 polymorphisms in 35 genes involved in drug metabolism/ transport have been selected. The application tests the hypotheses that the risk of treatment-related SMNs is associated with specific therapeutic exposures, variants in drug-metabolizing genes, drug transport genes, DNA repair genes, and the joint effects of specific therapeutic exposures with these susceptibility genes. The application will examine main effects of therapeutic exposures and genes for risk of SMNs and of its histologic and cytogenetic subtypes, and will also examine the role of gene-gene and gene-environment interactions in SMN development. This application's innovation lies in using a comprehensive and biologically plausible candidate gene approach to examine genetic variants in combination with well-known therapeutic exposures associated with SMNs. The application will enhance our understanding of the pathogenesis of SMN, and facilitate identification of cancer survivors at high-risk for development of SMNs, in turn facilitating primary prevention (individualizing therapy in future cancer populations) and secondary prevention (targeted screening, behavior modification, chemoprevention in survivors). Identification of pertinent genes and pathways will provide critical information regarding pathogenesis of SMN, with potential application to de novo cancer.